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GeneBe

7-37907573-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_003014.4(SFRP4):c.947C>A(p.Pro316Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,613,730 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 5 hom. )

Consequence

SFRP4
NM_003014.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.46
Variant links:
Genes affected
SFRP4 (HGNC:10778): (secreted frizzled related protein 4) Secreted frizzled-related protein 4 (SFRP4) is a member of the SFRP family that contains a cysteine-rich domain homologous to the putative Wnt-binding site of Frizzled proteins. SFRPs act as soluble modulators of Wnt signaling. The expression of SFRP4 in ventricular myocardium correlates with apoptosis related gene expression. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.019921035).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000762 (116/152222) while in subpopulation NFE AF= 0.00128 (87/68020). AF 95% confidence interval is 0.00106. There are 0 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SFRP4NM_003014.4 linkuse as main transcriptc.947C>A p.Pro316Gln missense_variant 6/6 ENST00000436072.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SFRP4ENST00000436072.7 linkuse as main transcriptc.947C>A p.Pro316Gln missense_variant 6/61 NM_003014.4 P1
SFRP4ENST00000478975.1 linkuse as main transcriptn.315C>A non_coding_transcript_exon_variant 2/22

Frequencies

GnomAD3 genomes
AF:
0.000763
AC:
116
AN:
152104
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000411
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000786
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00128
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000581
AC:
146
AN:
251350
Hom.:
0
AF XY:
0.000530
AC XY:
72
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.000431
Gnomad AMR exome
AF:
0.00101
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000879
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.00135
AC:
1969
AN:
1461508
Hom.:
5
Cov.:
32
AF XY:
0.00127
AC XY:
921
AN XY:
727074
show subpopulations
Gnomad4 AFR exome
AF:
0.000359
Gnomad4 AMR exome
AF:
0.00123
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00167
Gnomad4 OTH exome
AF:
0.000812
GnomAD4 genome
AF:
0.000762
AC:
116
AN:
152222
Hom.:
0
Cov.:
32
AF XY:
0.000726
AC XY:
54
AN XY:
74430
show subpopulations
Gnomad4 AFR
AF:
0.000409
Gnomad4 AMR
AF:
0.000785
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00128
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000903
Hom.:
0
Bravo
AF:
0.000960
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.000478
AC:
58
EpiCase
AF:
0.000818
EpiControl
AF:
0.00124

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 09, 2021The c.947C>A (p.P316Q) alteration is located in exon 6 (coding exon 6) of the SFRP4 gene. This alteration results from a C to A substitution at nucleotide position 947, causing the proline (P) at amino acid position 316 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 15, 2022This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 316 of the SFRP4 protein (p.Pro316Gln). This variant is present in population databases (rs147145122, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SFRP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1377522). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.21
T
Eigen
Benign
-0.063
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.73
T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.020
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.69
N
MutationTaster
Benign
1.0
D;N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.33
N
REVEL
Benign
0.075
Sift
Benign
0.052
T
Sift4G
Benign
0.21
T
Polyphen
0.0
B
Vest4
0.13
MVP
0.81
MPC
0.37
ClinPred
0.021
T
GERP RS
5.8
Varity_R
0.049
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147145122; hg19: chr7-37947175; API